Controlled, non-linear focused ultrasound treatment

ABSTRACT

A system for treating tissue within a body is configured to deliver a first level of ultrasound energy to a target tissue region for a first duration resulting in the generation of microbubbles in the target tissue region, determine one or more characteristics of the target tissue region in the presence of the microbubbles, and deliver a second level of ultrasound energy to the target tissue region for a second duration, wherein one or both of the second energy level and the second duration are based, at least in part, on the determined one or more characteristics of the target tissue region.

FIELD OF INVENTION

The present invention relates generally to apparatus and methods for delivering focused ultrasound energy to targeted tissue regions in a patient's body.

BACKGROUND

High intensity focused ultrasonic energy (i.e., having a frequency greater than about 20 kilohertz), may be used therapeutically to treat internal tissue regions within a patient. For example, ultrasonic waves may be used to induce coagulation and/or necrosis in a target tissue region, such as a tumor. In this process, the ultrasonic energy is “absorbed” by the tissue, causing the generation of heat. The absorbed energy heats the tissue cells in the target region to temperatures that exceed protein denaturation thresholds, usually above 60° C., resulting in coagulation and/or necrosis of the tissue in the target region.

During a focused ultrasound procedure, small gas bubbles, or “microbubbles,” may be generated in the liquid contained in the tissue, e.g., due to the stress resulting from negative pressure produced by the propagating ultrasonic waves and/or from when the heated liquid ruptures and is filled with gas/vapor. On the one hand, the microbubbles have the positive treatment effect by generating higher harmonic frequencies of the original wave energy, thereby greatly increasing the absorption of energy in the tissue, and by multiple reflection that extends the acoustic pass in the target region. On the other hand, the reaction of tissue containing a higher relative percentage of microbubbles to the continued application of the ultrasound energy is non-linear and difficult to predict. For example, the microbubbles may collapse due to the applied stress from an acoustic field. This mechanism, called “cavitation,” may cause extensive tissue damage beyond that targeted, and may be difficult to control.

SUMMARY OF THE INVENTION

In accordance with one embodiment of the invention, a method of treating tissue within a body includes delivering a first level of ultrasound energy to a target tissue region for a first duration resulting in the generation of microbubbles in the target tissue region, determining one or more characteristics of the target tissue region in the presence of the microbubbles, and delivering a second level of ultrasound energy to the target tissue region for a second duration, wherein one or both of the second energy level and the second duration are based, at least in part, on the determined one or more characteristics of the target tissue region.

In accordance with another embodiment of the invention, a system for treating tissue within a body includes means for delivering a first level of ultrasound energy to a target tissue region for a first duration resulting in the generation of microbubbles in the target tissue region, means for determining one or more characteristics of the target tissue region in the presence of the microbubbles, and means for delivering a second level of ultrasound energy to the target tissue region for a second duration, wherein one or both of the second energy level and second duration are based, at least in part, on the determined one or more characteristics of the target tissue region.

In accordance with still another embodiment of the invention, a controller for a focused ultrasound system, the focused ultrasound system having a plurality of transducer elements for delivering ultrasound energy to a target tissue region in a patient's body, the controller configured to cause the delivery of a first level of ultrasound energy to the target tissue region for a first duration resulting in the generation of microbubbles in the target tissue region, determine one or more characteristics of the target tissue region in the presence of the microbubbles, and cause the delivery of a second level of ultrasound energy to the target tissue region for a second duration, wherein one or both of the second ultrasound energy level and the second duration are based, at least in part, on the determined one or more characteristics of the target tissue region.

Other aspects and features of the invention will be evident from reading the following detailed description of the illustrated embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments of the invention are described hereinafter with reference to the accompanying figures. It should be noted that the figures are not drawn to scale and elements of similar structures or functions are represented by like reference numerals throughout the figures. It should also be noted that the figures are only intended to facilitate the description of the illustrated embodiments, and are not intended as an exhaustive illustration or description thereof.

FIG. 1A illustrates an exemplary focused ultrasound system, including an ultrasound transducer for focusing ultrasonic energy at a target tissue region within a patient.

FIG. 1B is a cross-sectional detail of the ultrasonic transducer and target tissue region of FIG. 1A, illustrating microbubbles generated in tissue located in a focal zone of the transducer.

FIG. 2 is a cross-sectional view of a target tissue mass, illustrating a series of planned sonication areas.

FIG. 3 illustrates a method for constructing a treatment plan using the system of FIG. 1A, in accordance with some embodiments of the invention.

FIG. 4 illustrates a method for treating tissue using microbubbles to enhance heating of the target tissue region, in accordance with some embodiments of the invention.

FIGS. 5A and 5B are two-dimensional representations of a target sonication area, illustrating instances in which the actual thermal ablation is either greater than (FIG. 5A), or less than (FIG. 5B), a predicted amount.

FIG. 6 illustrates an exemplary comparison of actual versus predicted thermal doses for a target tissue region.

FIG. 7 illustrates a method of controlling thermal dosing in accordance with some embodiments of the invention.

FIG. 8 illustrates a method for updating a treatment plan in accordance with some embodiments of the invention.

DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS

FIG. 1A illustrates a focused ultrasound system 10 in accordance with some embodiments. The system 10 includes an ultrasound transducer 14, drive circuitry (driver) 16 coupled to the transducer 14, a controller 18 coupled to the driver 16, an imaging device 20, and a processor 22 coupled to the imaging device 20 and the controller 18. The transducer 14 may direct acoustic energy represented by beam 15 towards a target 42, typically a tumor or other tissue region, within a patient 40. The beam 15 may be used to coagulate, generate mechanical damage, necrose, heat, or otherwise treat the target 42, which may be a benign or malignant tumor within an organ or other tissue structure (not shown). The system 10 also includes a user interface (UI) 23, such as a screen, keyboard, a mouse, a button, a touch pad, and the like, for allowing a user to input data, such as treatment parameters, to the processor 22. The user interface 23 is shown as a separate component from the processor 22. Alternatively, the user interface 23 can be integrated with the processor 22.

The transducer 14 includes multiple piezoelectric elements 24 together providing a transducer array. Alternatively, the transducer 14 may include a single piezoelectric transducer element. In some embodiments, the transducer 14 may have a concave or bowl shape, such as a “spherical cap” shape, i.e., having a substantially constant radius of curvature such that the transducer 14 has an inside surface defining a portion of a sphere. Alternatively, the transducer 14 may have a substantially flat configuration (not shown), and/or may include an outer perimeter that is generally, but not necessarily, circular. The transducer 14 may be divided into any desired number of elements (not shown).

In alternative embodiments, the transducer 14 may include one or more transducer elements 24 having a variety of geometric shapes, such as hexagons, triangles, squares, and the like, and may be disposed about a central axis, preferably but not necessarily, in a substantially uniform or symmetrical configuration. In the illustrated embodiments, each of the transducer elements 24 may be a one-piece piezoceramic part, or alternatively, be composed of a mosaic arrangement of a plurality of small piezoceramic elements (e.g., phased array). The piezoceramic parts or the piezoceramic elements may have a variety of geometric shapes, such as hexagons, triangles, squares, and the like. Alternatively the transducer could be built from other materials that are capable to produce high power acoustic wave. The transducer elements 24 can be time-delayed or phase-delayed driven. Delay elements (not shown), well known in the art, may be coupled to respective transducer elements 24 for providing delay times for the respective transducer elements 24 such that the delivered acoustic waves by the transducer elements 24 focuses onto the zone 38. If the transducer elements 24 include a plurality of elements, each element may be coupled to a respective delay element. The delay elements may be implemented as a part of the ultrasound transducer device 14, the driver 16, or the controller 18.

In some embodiments, the transducer elements 24 can be movably secured to a structure (not shown) such that the position and/or shape of the focal zone 38 can be varied during use. In such cases, the transducer device 14 includes a positioner for moving the transducer elements 24. The positioner may be configured to move the transducer 14 in one or more directions, and preferably in any of three orthogonal directions. The positioner can, for examples, include a motor, such as an electric motor or a piezoelectric motor, a hydraulic, or a gimbal system. In some embodiments, the structure can include a plurality of movable sections to which one or more of the transducer elements 24 are secured. In such cases, the movable sections are installed on respective gimbals, and the transducer elements 24 are movable by operation of the gimbals. The transducer elements 24 can be configured to move in one degree of freedom, or in multiple degree of freedoms (e.g., two to six degree of freedoms). A focal distance (a distance from the transducer 14 to a focal zone 38 of the acoustic energy emitted by the transducer 14) may be adjusted electronically, mechanically, or using a combination of mechanical and electronic positioning, as is known in the art.

The actual configuration of the transducer 14, however, is not important for purposes of understanding the embodiments of the present invention, and any of a variety of ultrasound transducers may be used, such as flat circular arrays, linear arrays, and the like.

The transducer 14 may be mounted within a casing or chamber (not shown) filled with degassed water or acoustically transmitting fluid. The chamber may be located within a table (not shown) upon which a patient 40 may be positioned, or within a fluid-filled bag mounted on a movable arm that may be placed against a patient's body. The contact surface of the chamber, generally includes a flexible membrane (not shown) that is substantially transparent to ultrasound. For examples, the flexible member may be constructed from mylar, polyvinyl chloride (PVC), or other suitable plastic material. A fluid-filled bay (not shown) may be provided on the membrane that may conform easily to the contours of the patient 40 positioned on the table, thereby acoustically coupling the patient 40 to the transducer 14 within the chamber. In addition or alternatively, acoustic gel, water, or other fluid may be provided between the patient 40 and the membrane to facilitate further acoustic coupling between the transducer 14 and the patient 40.

In the illustrated embodiments, the transducer elements 24 are coupled to the driver 16 and/or controller 18 for generating and/or controlling the acoustic energy emitted by the transducer elements 24. For example, the driver 16 may generate one or more electronic drive signals, which may be controlled by the controller 18. The transducer elements 24 convert the drive signals into acoustic energy 15, which may be focused using conventional methods. The controller 18 and/or driver 16 may be separate or integral components. It will be appreciated by one skilled in the art that the operations performed by the controller 18 and/or driver 16 may be performed by one or more controllers, processors, and/or other electronic components, including software and/or hardware components. The terms controller and control circuitry may be used herein interchangeably, and the terms driver and drive circuitry may be used herein interchangeably.

The driver 16, which may be an electrical oscillator, may generate drive signals in the ultrasound frequency spectrum, e.g., as low as fifty kilohertz (20 KHz), or as high as ten megahertz (10 MHz), and more preferably, between 0.1 to 10 MHz. Preferably, the driver 16 provides drive signals to the transducer elements 24 at radio frequencies (RF), for example, between about a hundred Kiloherz to ten Megahertz (0.1-10 MHz), and more preferably between 200 Kilohertz and three Megahertz (0.20 and 3.0 MHz). However, in other embodiments, the driver 16 can also be configured to operate in other ranges of frequencies. When the drive signals are provided to the transducer elements 24, the transducer elements 24 emit acoustic energy 15 from their respective exposed surfaces, as is well known to those skilled in the art.

The controller 18 may control a phase component of the drive signals to respective elements 24 of the transducer 14, e.g., to control a shape of a focal zone 38 generated by the transducer 14 and/or to move the focal zone 38 to a desired location. For example, the controller 18 may control the phase shift of the drive signals based upon a radial position of respective transducer elements 24 of the transducer 14, e.g., to adjust a focal distance, or to adjust phases to control the focus lateral position. In addition or alternatively, the controller 18 may control the positioning system to move the transducer 14, and consequently, the location of the focal zone 38 of the transducer 14, to a desired location (e.g., within the target tissue region 42). In some embodiments, the controller 18 may also control a frequency of the drive signals.

The controller 18 may control amplitude (and/or other aspects) of the drive signals, and therefore, the intensity or power of the acoustic waves transmitted by the transducer elements 24. For example, the controller 18 may cause the drive circuitry 16 to provide drive signals to the transducer 14 above a threshold such that the acoustic energy emitted by the transducer 14 may generate microbubbles in fluid within tissue in the focal zone 38. Subsequently, the controller 18 may lower the intensity below a threshold to a level at which the generation of microbubbles is minimized in the tissue within the focal zone 38, yet may still necrose, coagulate, or otherwise heat tissue, as explained below. For example, the controller 18 may subsequently lower the intensity to approximately 0 to thereby prevent further formation of microbubbles at the focal zone 38 during a treatment process.

In some embodiments, the controller 18 is also used to control respective transducer elements 24 to protect a tissue region (e.g., healthy tissue that is adjacent the target tissue 42, at the far field relative to the target tissue 42, or at the near field relative to the target tissue 42), while treating the target tissue. Particularly, the controller 18 is configured to control an amplitude, a phase, a frequency, or a combination thereof, of respective transducer elements 14, such that an energy intensity at the target tissue 42 is above a prescribed threshold (treatment threshold) level sufficient to treat the target tissue 42, while an energy intensity at tissue (sensitive tissue) desired to be protected is below a prescribed threshold (safety threshold) level for protection of the sensitive tissue. For examples, the controller 18 can generate a drive signal to reduce an energy delivered to the sensitive tissue by one of the transducer elements 24, or not activate one of the transducer elements 24, thereby creating a zone of relatively lower energy at the sensitive tissue. As used herein, the term, “sensitive tissue”, refers to tissue that is desired to be protected, and should not be limited to tissue have a certain sensitivity.

In the illustrated embodiments, the imaging device 20 is configured for obtaining image data of at least a portion of the target region 42 before or while treating the patient 40. For example, the imaging device 20 may be a magnetic resonance imaging (MRI) device, such as that disclosed in U.S. Pat. Nos. 5,247,935, 5,291,890, 5,368,031, 5,368,032, 5,443,068 issued to Cline et al., and U.S. Pat. Nos. 5,307,812, 5,323,779, 5,327,884 issued to Hardy et al., the disclosures of which are expressly incorporated by reference herein. In other embodiments, the imaging device 20 can be another type of device capable of performing an imaging of tissue, such as, a x-ray device, a fluoroscope, an ultrasound imaging device, or a computed tomography machine. Although the imaging device 20 is shown separated from the transducer device 14, in alternative embodiments, the imaging device 20 can be a component of, or integrated with, the transducer device 14. For example, the imaging device 20 can be secured to a center of the transducer device 14 in some embodiments. Also, the term “image” as used herein is intended to include image data that may be stored in a circuitry or a computer-readable medium, and is not limited to image data that is displayed to be visually perceived.

During use of the system 10, image data obtained from the imaging device 20 are transmitted to processor 22 for processing. In some embodiments, the processor 22 can be a computer, or a component of a computer. As used herein, the term, “computer” is not limited to desktop computers and laptops, and include any device capable of performing the functions described herein. For example, the processor 22 can be a general purpose processor, or an application specific processor (e.g., an ASIC processor, DSP, etc.). In further embodiments, the processor 22 can be a software (an example of a computer product), or a combination of a software and a hardware. In FIG. 1A, the processor 22 is shown as a separate component from the driver 16 and the controller 18. Alternatively, the processor 22 can be a component of the driver 16, and/or a component of the controller 18.

After receiving image data from the imager 20, the processor 22 may use the image data to construct a treatment plan, in which case, the processor 22 functions as a planner. When functioning as a planner, the processor 22 automatically constructs a treatment plan, which consists of a series of treatment site represented by thermal dose properties. The purpose of the treatment plan is to ensure complete ablation of target mass 42 by planning a series of sonications that will apply a series of thermal doses at various points within target mass 42, resulting in a composite thermal dose sufficient to ablate the entire mass 42.

For example, the plan will include the location, frequency, duration, and power of the sonication and the position and mode of the focal spot for each treatment site in series of treatment sites. The mode of the focal spot refers to the fact that the focal spot can be of varying dimensions. Typically, there will be a range of focal modes from small to large with several intermediate modes in between. The actual size of the focal spot will vary, however, as a function of the focal distance (l), the frequency, and focal spot dispersion mode that could be generated by spatial dithering of the focus or by shaping of the focus acoustically. While planning, the processor 22 may take the tissue data in the pass zone, types of tissues, frequency, mode and focal spot size variation into account when planning the position of the focal spot for a treatment site, the required power level and energy level. The treatment plan is then passed to the controller 18 in the relevant format to allow the controller 18 to perform its tasks.

In order to construct the treatment plan, the processor 22 uses input from the user interface 23 and the imager 20. For example, in one implementation, a user specifies the target volume, the clinical application protocol, i.e., breast, pelvis, eye, prostate, etc., via the user interface 23. Selection of the clinical application protocol may control at least some of the default thermal dose prediction properties such as thermal dose threshold, thermal dose prediction algorithm, maximum allowed energy density, thermal dose for different treatment site, cooling time between thermal doses, etc.

In other implementations, some or all of these properties are input through the user interface 23 as user specified thermal dose prediction properties. Other properties that may be input as user specified thermal dose prediction properties are the sonication grid density (how much the sonications should overlap) and the physical parameters of transducer 14. The latter two properties may also be defined as default parameters in certain implementations. Additionally, a user may edit any of the default parameters via the user interface 23. In one implementation, user interface 23 comprises a Graphical User Interface (GUI): A user employs a mouse or touch screen to navigate through menus or choices as displayed on a display device in order to make the appropriate selections and supply the required information.

To further aid the processor 22 in constructing the treatment plan, the imager 20 supplies image data of the target mass 42 that can be used to determine volume, position, and distance from a skin surface 25 (FIG. 1B). In one implementation, the imager 20 is a MRI device and the images provided are three-dimensional images of the target mass 42. Once the processor 22 receives the input from the user interface 23 and the image data from the imager 20, the processor 22 automatically constructs the treatment plan.

As illustrated in FIG. 2, the goal of the treatment plan is to completely cover a target tissue mass 42, and a predefined margin around it if so desired, by delivering a series of sonications to treat a plurality of portions 80 of the target tissue mass 42, so that the entire target mass 42 is fully ablated. In one implementation, once the treatment plan is constructed, a user may, if required, edit the plan by using the user interface 23. In one implementation, the processor 22 will also produce a predicted thermal dose distribution. This distribution is similar to the distribution illustrated in FIG. 2, wherein the predicted thermal doses are mapped onto images of target mass 42 provided by the imager 20. In one implementation, the distribution is a three-dimensional distribution. In some embodiments, an algorithm is included in the processor 22 that limits the peak temperature of the focal zone 38. The algorithm is referred to as the dose predictor.

In one implementation, the treatment plan is a three-dimensional treatment plan. FIG. 3 illustrates one preferred process flow diagram for constructing a three-dimensional treatment plan, using three-dimensional images of the target mass 42 and a three-dimensional predicted thermal dose distribution. The ability of focusing at different focal lengths (l) leads to variable focal spots and variable lesion sizes in the target mass 42 as a function of (y), the transducer axis (FIG. 1B). Therefore, as a result of the process illustrated in FIG. 3, the processor 22 finds a minimum number of overlapping cross-sectional treatment layers required to ablate a portion of the target mass 42 extending from y_(near) to y_(far). The processor 22 may also predict the lesion size in the cross-sectional layer and will provide the maximal allowed energy in each layer, taking into account the maximum allowed temperature rise. The energy or power will be normalized among different layers, such that the maximal temperature at the focus remains approximately constant throughout the treatment zone.

Constructing the three-dimensional treatment plan begins in step 102 with obtaining diagnostic quality images of the target mass 42. For example, the diagnostic quality images may be the preliminary images supplied by an imager such as the imager 20. In step 104, the processor 22 uses the diagnostic images to define the treatment region, or the user may define it through the user interface 23. Then, in step 106, a line y[y_(near):y_(far)] is defined such that (y) cuts through target zone perpendicular to the transducer 14 along the transducer axis from the nearest point within the target mass 42 (y_(near)) to the furthest point (y_(far)). Line (y) will be the axis along which the treatment layers will be defined.

Once (y) is defined, the processor 22 will perform a dose prediction in step 108 using the maximal power required for small and large spot sizes at (y_(far)) In step 110, the processor 22 determines if the resulting maximal temperature exceeds the allowed limit. It should be noted that properties such as the maximal power and the maximal temperature limit may be supplied as default thermal dose prediction properties or may be supplied as user supplied thermal dose prediction properties. If the resulting maximal temperature does exceed the allowable limit, the power is scaled down linearly in step 112 until the temperature elevation is within the allowable limit, or until some other predefined threshold is crossed.

The small and large focal modes may correspond to modes 0 and 4, respectively, with additional modes 1, 2 and 3 falling between modes 0 and 4. Therefore, in step 114, the processor 22 predicts the maximal power for the intermediate modes 1, 2 and 3, from the scaled max powers at modes 0 and 4. Thus, in step 116, if there are further modes, the processor 22 reverts to step 108 and predicts the maximal power for these modes. If it is the last mode for (y_(far)) then the processor 22 uses the same scaled max power, as in step 118, to find the corresponding maximal powers for each focal mode at (y_(near)). Then in step 120, the processor 22 finds the maximal temperature elevation and lesion size for the appropriate mode and the required maximal power at a point (y₁), such that y_(near)<y₁<y_(far). Preferably, (y₁) is close to (y_(near)). For example, in one implementation, y₁=y_(near)+25 mm. If the temperature elevation at (y₁) exceeds the allowable limit as determined in step 122, then in step 124 the power is scaled down until the temperature elevation is within the limit, and then the processor 22 determines the resulting lesion size at (y₁).

Using an overlap criterion with respect to the (y_(near)) boundary, which may be provided via a sonication grid density, the first treatment is placed (step 126). Of course, the treatment will actually be a three-dimensional volume. Then, in step 128, using an inter-layer overlap criterion, an auxiliary treatment slice is placed on top of the previous treatment layer using the same height for the second slice as for the first slice. In step 130, the processor 22 determines if more layers are needed to reach (y_(far)). If more layers are needed, then the process reverts to step 118, and (y₁) replaces (y_(near)) (step 132) in the algorithm.

Once the last treatment layer is reached, the processor 22 will determine if the layer extends beyond the target limit (y_(far)). If the layer does extend too far, then the overlap criterion should be used with the outer limit (y_(far)) as a boundary instead of the previous layer. Using (y_(far)) in the overlap criterion may cause overdose but will not damage healthy tissue outside target mass 42. In one implementation, the thermal dose properties are automatically optimized using physiological parameters as the optimization criterion. For example, mechanical tissue parameters like compressibility, stiffness, and scatter, may be used.

It should be noted that the method of determining a treatment plan should not be limited by the above example, and that other techniques known in the art may also be used to determine a treatment plan as an example non-layer based planning. Also, in other embodiments, the processor 22 does not construct the treatment plan. Instead, the processor 22 is configured to receive a pre-determined treatment plan via an input (e.g., a disk drive, a cable port, a USB port, a phone port, a memory slot, etc.).

After a treatment plan has been obtained, the system 10 can then be used to treat the patient 40. During use, the patient 40 may be positioned on the table with water, acoustically conductive gel, and the like applied between the patient 40 and the bag or membrane, thereby acoustically coupling the patient 40 to the transducer 14. The transducer 14 may be focused towards a target tissue region 38 within a tissue 42, which may, for example, be a cancerous or benign tumor. The transducer 14 may be activated by supplying a set of drive signals at one or more frequencies to the transducer 14 to focus acoustic energy at the target tissue 42, represented by energy beam 15. As the acoustic energy 15 passes through the patient's body, a fraction of the acoustic energy 15 is converted to heat, which may raise the temperature of the target tissue 42. The acoustic energy 15 may be focused on the target tissue 42 to raise the temperature of the target tissue 42 sufficiently to coagulate and/or necrose the tissue 42, while minimizing damage to surrounding healthy tissue.

In order to optimize a therapeutic procedure, the system 10 may be operated to achieve a maximal coagulation rate (coagulated tissue volume/time/energy) in the target tissue 42, while minimizing heating in the surrounding tissue, particularly within the near field region 52, as well as in the far field. The coagulation rate may be optimized by achieving preferential absorption of the ultrasonic waves, where the absorption by the tissue within the focal zone 38 is higher than the tissue outside the focal zone 38. The presence of microbubbles 56 in tissue within the focal zone 38 (shown in FIG. 1B) may achieve this goal, because tissue including microbubbles 56 therein may have a higher energy absorption coefficient than then surrounding tissue without microbubbles.

FIG. 4 illustrates an overview of a method 200 for heating tissue within a target region, e.g., to induce tissue coagulation and/or necrosis during a sonication that includes a series of acoustic energy transmissions at different intensities. Initially, a target tissue 42, e.g., a benign or malignant tumor within an organ, such as a liver, kidney, uterus, breast, brain, and the like, may be selected for treatment. At step 202, ultrasonic waves above a certain threshold intensity may be directed towards the target tissue structure 42 to generate microbubbles 56 within focal zone 38. Although this threshold intensity may differ with each patient and/or tissue structure, appropriate threshold intensities may be readily determined by those skilled in the art, e.g., through the use of a monitoring mechanism sensitive to the generation of micro-bubbles.

Transmission of acoustic energy at the intensity above the threshold level may be relatively brief, e.g., having a duration of about three seconds or less, and preferably having a duration of not more than about 0.1-0.5 second, yet sufficiently long to generate microbubbles within the focal zone 38 without substantially generating microbubbles in tissue outside the focal zone 38, e.g., in the near field 52 (shown in FIG. 1B). The generated microbubbles in the focal zone 38 oscillates at the frequency of the delivered acoustic wave, and assists in extending the acoustic pass in the focus area by multiple reflections and/or, acting as non linear multipliers receiving energy at a lower frequency and transmitting it back at a higher frequencies and/or generating some limited local cavitation hence enhancing absorption of the energy at the focal volume, thereby allowing tissue within the focal zone 38 to be heated faster and more efficiently.

At step 204, the intensity of the beam 15 may be lowered below the threshold level and, maintained at a lower intensity while the beam 15 remains focused substantially at the focal zone 38 so as to heat the tissue within the focal zone 38 without collapsing the microbubbles 56 within the focal zone 38 or the following transmission could be spaced in time and be with short enough duration to allow partial bubbles dissipation and minimize collapse the bubbles collapse as a result of the acoustic beam or eventually dissipate back into the tissue. By way of one example, this lower intensity level may be reduced below the intensity used to generate the microbubbles 56 by a factor of about two to three. The transmission at this lower intensity may have a substantially longer duration as compared to the transmission at the higher intensity used to generate the microbubbles 56. By way of another example, the acoustic energy may be transmitted for at least about two or three seconds (2-3 s.), and preferably about eight to ten seconds (8-10 s.). By way of further example, microbubbles 56 generated within tissue may be present for as little as eight to ten seconds (8-10 s.), e.g., due to natural perfusion of the tissue. Thus, the acoustic energy may be maintained for as long as sufficient supply of microbubbles are present. Because of the microbubbles 56, acoustic energy absorption by the tissue within the focal zone 38 may be substantially enhanced, as explained above.

At step 206, the controller 18 may determine whether the sonication has been sufficiently long to heat the tissue within the focal zone 38 to a desired level, e.g., to coagulate or otherwise necrose the tissue within the focal zone 38. If not, additional microbubbles may be generated in the target tissue region, e.g., by repeating step 202, and then the intensity may be reduced to heat the tissue while avoiding causing collapse of microbubbles, e.g., by repeating step 164 or by using temporally spaced short high power transmissions. Steps 202 and 204 may be repeated periodically, e.g., one or more times, during the sonication until sufficient time has passed to substantially ablate or otherwise treat the tissue within the focal zone 38.

Thus, a single sonication, which may last between one and twenty seconds (1-20 s.), and preferably, about ten seconds (10 s.) or more, may include multiple transmissions above and below the threshold necessary to generate microbubbles. For example, after perfusion has at least partially dispersed the microbubbles from the tissue within the focal zone 38, transmission at an intensity above the threshold level may be repeated in order to maintain a level of microbubble density sufficient to create preferential absorption of the tissue within the focal zone. Transmission of acoustic energy at an intensity below the threshold level may then be repeated to cause heating of the tissue within the focal zone without causing bubble collapse. The intensity levels of the acoustic energy may be set to switch between an increment above and an increment below the threshold intensity, or to switch between on and off periods. Alternatively, the intensities may be varied during the course of the sonication. This alternating sequence of acoustic transmissions may be localized and timed in such a way as to create and maintain a microbubble “cloud” in the target tissue 42 to optimize the coagulation process.

This alternating sequence during a single sonication may provide several advantages as compared to conventional focused ultrasound (“FUS”) ablation without microbubbles. For example, if an intensity level is utilized in the heating, while minimizing the bubble collapse step (step 204) that is comparable to conventional FUS ablation, a substantially larger focal zone 38 may created. For example, due to the enhanced energy absorption, the resulting focal zone 38 may be about two to three times larger than conventional FUS ablation utilizing the same energy, thereby necrosing or otherwise heating a larger volume of tissue within the target tissue 42. This increased ablation volume may result in requiring fewer sonications to ablate an entire target tissue 42.

Alternatively, a lower intensity level may be used as compared to conventional FUS, thereby generating a comparably sized focal zone while using substantially less energy. This may reduce energy consumption by the system 10 and/or may result in substantially less energy being absorbed by surrounding tissue, particularly in the near field 52. With less energy absorbed, cooling times between sonications may be substantially reduced. For example, where conventional FUS may require ninety seconds or more of cooling time between sonications, systems and methods in accordance with embodiments described herein may allow cooling times of about forty seconds or less.

Thus, in either case, an overall treatment time to ablate or otherwise treat a target tissue structure may be substantially reduced as compared to conventional FUS without microbubbles.

Upon completing the sonication, the transducer 14 may be deactivated, e.g., for sufficient time to allow heat absorbed by the patient's tissue to dissipate. The transducer 14 may then be focused on another portion of the target tissue region 42, e.g., adjacent the previously treated tissue, and the process 200 is repeated for another portion of the target tissue region 42. Alternatively, the acoustic beam 15 may be steered continuously or discretely without any cooling time, e.g., using a mechanical positioner or electronic steering.

Sometimes, the actual thermal dose delivered with a particular sonication may not be the same as the thermal dose predicted by the processor 22. For example, absorption coefficient, blood flow, uneven heat conduction, different rates of conduction for different tissue masses, tissue induced beam aberration, and variances in system tolerances, may make it difficult to accurately predict thermal dosages. Moreover, the actual focal spot dimensions are variable as a function of focal distance (l) and of focal spot dispersion, making accurate thermal dosing predictions even more difficult.

As illustrated in FIGS. 5A-B, two situations can occur. First, as illustrated by comparison 302 in FIG. 5A, actual thermal dose 306 may be larger than predicted thermal dose 308. In this case there will be an excess 310 of ablated tissue. The second situation is illustrated by comparison 304 in FIG. 5B. In this case, actual thermal dose 306 is smaller than predicted thermal dose 308. Therefore, there is an area 312 of non-ablated tissue remaining after sonication.

In some embodiments, the processor 22 can use the image data from the imager 20 to monitor at least a portion of the target region 42 during a treatment process. For example, the imager 20 may provide real-time temperature sensitive magnetic resonance images of target mass 42 after some or all of the sonications. The processor 22 then uses the images from the imager 20 to construct an actual thermal dose distribution 400 comparing the actual composite thermal dose to the predicted composite thermal dose as illustrated in FIG. 6. In particular, thermal dose distribution 400 illustrates a comparison of the actual versus predicted thermal dose for each or some of the sonications. As can be seen, excess areas 310 and non-ablated areas 312 will result in over- or under-dosing as the thermal doses are applied to different treatment sites 414 within the target tissue 42.

In one implementation, the image data provided by the imager 20 and the updated thermal dose distributions 400 represent three-dimensional data. The processor 22 uses thermal dose distribution 400 to automatically adjust the treatment plan in real-time after each sonication, or uses the thermal dose distribution 400 in some of the points to adjust for the neighboring points. The processor 22 can adjust the treatment plan by adding treatment sites, removing treatment sites, or continuing to the next treatment site. Additionally, the thermal dose properties of some or all remaining treatment sites may automatically be adjusted by the processor 22 based on real-time feedback from the imager 20.

In some embodiments, the processor 22 may reformulate the treatment plan automatically after each thermal dose or after some of the sonications, thus ensuring that the target tissue 42 is completely ablated in an efficient and effective manner. In addition, the feedback provided by the imager 20 might be used to manually adjust the treatment plan or to override the changes made by the processor 22.

A method 500 of treating tissue that involves controlling thermal dosing is illustrated in FIG. 7. Initially, a user selects an appropriate clinical application protocol in step 502. For example, a user may use an interface such as the user interface 23 to select the clinical application protocol. In some embodiments, selecting the clinical application protocol controls a set of default thermal dose prediction parameters. After the clinical application is selected, relevant magnetic resonant images of a target mass (e.g., the target tissue 42) are retrieved in step 504. For example, the images may be retrieved by the imager 20. In step 506, the images are used to define a target region such as a treatment slice.

In some embodiments, defining the target region involves manually or automatically tracing the target mass onto the images retrieved in step 504. In one implementation, the target mass is traced in three dimensions onto three-dimensional images for three-dimensional treatment planning. In other embodiments that uses ultrasound, an operator is allowed to account for obstacles such as bones, gas, or other sensitive tissue, and plan accordingly to ensure that the ultrasound beam 15 will not pass through these obstacles. Based on this planning, a patient may be repositioned or the transducer 14 may be repositioned and/or tilted in order to avoid the obstacles.

In step 508, the user may enter additional thermal dose prediction properties or modify any default thermal dose prediction properties already selected. For example, these additional properties may be entered via the user interface 23. Then in step 510, a treatment plan is automatically constructed based on the properties obtained in the previous steps. The purpose of the treatment plan is to ensure a proper composite thermal dose sufficient to ablate the target mass by applying a series of thermal doses to a series of treatment sites, automatically accounting for variations in the focal spot sizes and in the thermal dose actually delivered to the treatment site.

The treatment plan may, for example, be automatically constructed by the processor 22. For example, in some embodiments, the processor 22 may be configured to perform the method of FIG. 3 to create the treatment plan. In some embodiment, automatically constructing the treatment plan includes constructing an expected thermal dose distribution showing the predicted thermal dose at each treatment site within the target tissue 42. This thermal dose distribution may represent a three-dimensional distribution.

In step 512, the treatment plan may be edited by manual input. For example, the user interface 23 may be used to edit the treatment plan. In one embodiment, editing the plan may include adding treatment sites, deleting treatment sites, changing the location of some or all of the treatment sites, changing other thermal dose properties for some or all treatment sites, or reconstructing the entire plan. As illustrated by step 520, if the plan is edited, then the process reverts to step 508 and continues from there. Once the plan is set, then verification step 514 is performed. Particularly, verification is performed to ensure that the system 100 is properly registered with regard to the position of the focal spot relative to the patient 40 and the target tissue 42.

In some embodiments, verification comprises performing a low energy thermal dose at a predefined spot within the target tissue 42 in order to verify proper registration. In a following step, the verification could be repeated at full energy level to calibrate the dosing parameters. As illustrated by step 522, re-verification may be required depending on the result of step 514. In this case, the process reverts back to step 514 and verification is performed again. On the other hand, mechanical properties, such as position, relating to transducer 14 may need to be changed (step 520) and, therefore, the process may revert to step 508. In other embodiments, the method 500 does not include steps 512 and 514.

Once the verification is complete, the treatment plan is implemented in step 516. For example, the treatment plan may be implemented by performing the method 200 of FIG. 4 to treat one or more portions of the target tissue 42. In some embodiments, this step also comprises capturing temperature sensitive image sequences of the target tissue 42 as each step of the plan is being implemented. These images will illustrate the actual thermal dose distribution resulting from each successive thermal dose. The imager 20 may, for example, provide the temperature sensitive images that are used to construct the actual thermal dose distribution.

For example, the imaging device 20 can be used to acquire images taken along a two-dimensional image plane (or slice) passing through a portion of the focal zone 38. The acquired images are processed by the processor 22 to monitor a change in temperature of this portion of the target region 42. The tissue temperature changes measured from images acquired in one or more imaging planes are used to derive a three-dimensional thermal evolution of the entire focal zone 38. The thermal evolution is used to verify that a sufficient thermal dose for tissue destruction is reached in the focal zone 38, as well as to track which portions of the target region 42 have been destroyed. This information, in turn, is used by the ultrasound controller 18 for positioning (e.g., mechanically or electronically) the ultrasound energy beam 15 and focal zone 38 for successive sonications of the target region 42. Thus, it is critical that the thermal evolution of the three-dimensional focal zone 38 be accurate.

In step 518, the actual thermal dose distribution is compared with the predicted thermal dose distribution in order to determine how closely the actual treatments are tracking the treatment plan. Then in step 524, it is determined if the treatment can proceed to the next step (e.g., repeat step 516 to treat other portion(s) of the target tissue 42), or if changes must be made to the treatment plan (step 520). The changes may be accomplished manually or automatically, and may comprise adding treatment sites, deleting treatment sites, repeating treatment sites, or modifying specific thermal dose properties for some or all of the treatment sites.

One of a variety of methods may be used to change or update the treatment plan. For example, at the end of each thermal dose, there may be regions within the target layer that are not covered by accumulated dose contours. These untreated areas are separated into individual regions. Each of these regions is then sent through the process, beginning with step 506, resulting in an updated treatment plan constructed to treat the remaining regions. The process will repeat until there are no more untreated regions. By way of more specific background information relating to this process, relevant methods and systems for changing and updating a treatment are described in U.S. Pat. No. 6,618,620, the entire disclosure of which is incorporated by reference herein.

FIG. 8 illustrates an alternative method for updating the treatment plan does not include steps 510, 512, and 514 in FIG. 7. Instead, the system 10 accepts the target mass 42 to be treated. First, it is determined if there is an untreated region 614 (step 602). This may be performed after step 506 or 508. If there is, then treatment site 616 is selected in step 604, and thermal dose properties are estimated so as to deliver the appropriate thermal dose the treatment site 616. Then, in step 606, the thermal dose is applied to treatment site 616 resulting in a treated region 618. In step 608, the size of treated region is calculated and stored as a linked-list so that in step 610 the treated region can be subtracted from the untreated region 620 in order to determine the remaining untreated region. The process then reverts to step 602, and a new treatment site is selected. Once the entire target mass 614 is treated, there will not be any untreated regions and the process will exit.

Referring back to FIG. 7, after the treatment is complete, it is determined in step 526 whether to restart a treatment or to exit. Additionally, if there is insufficient information or a fatal error occurs in any of steps 504-516, the process will automatically go to step 526, where it can be decided to proceed with a new treatment plan or to terminate a treatment process.

As illustrated in the above embodiments, the imager 20 and the processor 22 provide feedback control to thereby allow the target tissue 42 to be treated efficiently and accurately using microbubbles, while protecting adjacent tissue desired to be protected. By using the imager 20 and the processor 22 to provide data on treatment location and damage volume, the system 10 or a user can control an ultrasound treatment that uses microbubbles, to thereby prevent, or at least reduce the risk of, irreversible tissue damage in non-targeted tissue.

Although particular embodiments have been shown and described, it should be understood that the above discussion is not intended to limit the present invention, and it will be obvious and apparent to those skilled in the art that various changes and modifications may be made to the illustrated embodiments without departing from the scope of the invention set forth in the following claims. Further, an aspect or an advantage described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced in any other embodiments even if not so illustrated. 

1. A method of treating tissue within a body, comprising: delivering a first level of ultrasound energy to a target tissue region for a first duration resulting in the generation of microbubbles in the target tissue region; determining one or more characteristics of the target tissue region in the presence of the microbubbles; and delivering a second level of ultrasound energy to the target tissue region for a second duration, wherein one or both of the second energy level and the second duration are based, at least in part, on the determined one or more characteristics of the target tissue region.
 2. The method of claim 1, wherein each of the first duration and second duration are between 0.05 to 3 seconds.
 3. The method of claim 1, wherein the second energy level is determined by adjusting one or more of a frequency, a phase, and an amplitude of a drive signal used to generate the first energy level in order to achieve a maximum coagulation volume while controlling a coagulation location.
 4. The method of claim 1, wherein the second level of ultrasound energy is delivered to a different focal location in the target tissue region than the first level.
 5. The method of claim 1, wherein the second level of ultrasound energy is based, at least in part, on maintaining a temperature of the target tissue region above a prescribed threshold temperature.
 6. The method of claim 1, wherein the second level of ultrasound energy is based, at least in part, on maintaining a temperature of the target tissue region below a prescribed threshold temperature.
 7. The method of claim 1, wherein the one or more characteristics of the target tissue region are determined, at least in part, by obtaining a temperature sensitive image of the target tissue region.
 8. The method of claim 1, wherein the one or more characteristics of the target tissue region are determined, at least in part, by obtaining an actual thermal dose distribution associated with the target tissue region, and comparing the obtained actual thermal dose distribution with a predicted thermal dose distribution.
 9. The method of claim 1, wherein the second ultrasound energy level is different from the first ultrasound energy level.
 10. The method of claim 1, further comprising repeating the steps of determining one or more characteristics of the target tissue region in the presence of microbubbles in the target tissue region, and delivering the second level of ultrasound energy to the target tissue region, until a desired effect on the target tissue region is achieved.
 11. A system for treating tissue within a body, comprising: means for delivering a first level of ultrasound energy to a target tissue region for a first duration resulting in the generation of microbubbles in the target tissue region; means for determining one or more characteristics of the target tissue region in the presence of the microbubbles; and means for delivering a second level of ultrasound energy to the target tissue region for a second duration, wherein one or both of the second energy level and second duration are based, at least in part, on the determined one or more characteristics of the target tissue region.
 12. A controller for a focused ultrasound system, the focused ultrasound system having a plurality of transducer elements for delivering ultrasound energy to a target tissue region in a patient's body, the controller configured to: cause the delivery of a first level of ultrasound energy to the target tissue region for a first duration resulting in the generation of microbubbles in the target tissue region; determine one or more characteristics of the target tissue region in the presence of the microbubbles; and cause the delivery of a second level of ultrasound energy to the target tissue region for a second duration, wherein one or both of the second ultrasound energy level and the second duration are based, at least in part, on the determined one or more characteristics of the target tissue region.
 13. The system of claim 12, wherein each of the first duration and second duration are between 0.05 to 3 seconds.
 14. The system of claim 12, wherein the second energy level is determined by adjusting one or more of a frequency, a phase, and an amplitude of a drive signal used to generate the first energy level in order to achieve a maximum coagulation volume while controlling a coagulation location.
 15. The system of claim 12, wherein the second level of ultrasound energy is delivered to a different focal location in the target tissue region than the first level.
 16. The system of claim 12, wherein the second level of ultrasound energy is based, at least in part, on maintaining a temperature of the target tissue region above a prescribed threshold temperature.
 17. The system of claim 12, wherein the second level of ultrasound energy is based, at least in part, on maintaining a temperature of the target tissue region below a prescribed threshold temperature.
 18. The system of claim 12, wherein the one or more characteristics of the target tissue region are determined, at least in part, by obtaining a temperature sensitive image of the target tissue region.
 19. The system of claim 12, wherein the one or more characteristics of the target tissue region are determined, at least in part, by obtaining an actual thermal dose distribution associated with the target tissue region, and comparing the obtained actual thermal dose distribution with a predicted thermal dose distribution.
 20. The system of claim 12, wherein the second ultrasound energy level is different from the first ultrasound energy level.
 21. The system of claim 12, wherein the controller is configured to repeat the processes of determining one or more characteristics of the target tissue region in the presence of microbubbles in the target tissue region, and delivering the second level of ultrasound energy to the target tissue region, until a desired effect on the target tissue region is achieved. 